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August 28, 2018

As the thymus shrinks, strong immune cells expand

CiRA scientists report a specific type of immune cell, CXCR3+ naÏve phenotype T cells, that could explain how immune function is maintained during the thymic involution seen with age, but also why the risk of inflammation increases.

The thymus is a vital yet unusual organ. Vital in that it is responsible for producing immune cells; unusual in that it is largest at childhood and progressively shrinks after puberty. The result is less T cell production, which should lead to a higher risk of infection or cancer. Scientists at CiRA provide a new explanation in a study published in the European Journal of Immunology for why this is not the case. They show that despite the smaller thymus, a specific subtype of T cells, one they call "CXCR3+ naÏve phenotype T cells", are generated elsewhere in the body. The relative increase of these cells helps maintain immune function with age, but also increases the risk of inflammation.

CiRA Professor Yoko Hamazaki, who researches the thymus and led the study, explains how the immune system avoids being compromised despite a shrinking thymus.

"The thymic output of naÏve T cells progressively decreases with age because of thymic involution. However, our immune system tries to compensate the decreased number of naÏve T cells by homeostatic proliferation," Hamazaki says.

To study the effect of homeostatic proliferation on naÏve T cells, she and her research team induced an accelerated form of homeostatic proliferation in adult mice by removing the thymus. To their surprise, they found that despite the drop in naÏve T cell number, the proportion of one specific subtype of T cells increased.

"Mice with accelerated homeostatic proliferation showed a decrease in naÏve T cells, but naÏve phenotype T cells that expressed CXCR3 stayed constant, meaning that CXCR3+ fraction was relatively increased," says scientist Aiko Kato, who was first author of the study.

CXCR3 signals recruit T cells to the infected site. The study found that maintaining the number of CXCR3+ naÏve phenotype T cells could keep the immune system operating efficiently despite the loss of overall naÏve T cells.

However, the relative increase of CXCR3+ naÏve phenotype T cells also had a detrimental effect. When the scientists transferred these cells into mice with a preexisting skin condition, the mice showed excessive inflammation compared with the transfer of other T cells. Consistently, these cells tended to express two known proinflammatory molecules, IFN-γ and TNF-α.

Importantly, the researchers also found that CXCR3+ naÏve phenotype T cells exist in humans and that the proportion was different between individuals.

Based on these observations, Hamazaki speculates that this difference could explain why some people are predisposed to higher levels of inflammation.

"As people age, they show more chronic inflammation, which can lead to metabolic diseases and autoimmune diseases. Increase of CXCR3 naÏve phenotype T cells may be one cause," she said.

Paper Details
  • Journal: European Journal of Immunology
  • Title: CXCR3high CD8+ T cells with naïve phenotype and high capacity for IFN-γ production are generated during homeostatic T-cell proliferation
  • Authors: Aiko Kato1,2,3, Akifumi Takaori-Kondo2, Nagahiro Minato1, and Yoko Hamazaki1,3
  • Author Affiliations:
    1. Department of Immunology and Cell Biology, Kyoto University Graduate School of Medicine, Kyoto University,
      Kyoto, Japan
    2. Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto University,
      Kyoto, Japan
    3. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
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